Atypical posterior reversible encephalopathy syndrome: A lentiform fork sign following transplantation

Key Clinical Message Posterior Reversible Encephalopathy Syndrome, typically characterized by parieto‐occipital vasogenic edema, can present atypically, as a bilateral symmetrical vasogenic edema in the basal ganglia, featuring the called “lentiform fork sign.” Prompt recognition of such variations is crucial for accurate diagnosis and tailored management, highlighting the complexity of this syndrome's manifestations. Abstract Posterior Reversible Encephalopathy Syndrome (PRES) manifests as transient neurological symptoms and cerebral edema, commonly associated with immunosuppressive drugs (ISDs) in transplant recipients. ISDs can lead to endothelial dysfunction and compromise the blood–brain barrier. Typically, PRES exhibits identifiable MRI patterns, often demonstrating vasogenic edema in the bilateral parieto‐occipital white matter. Identifying unique presentations, such as the recently observed “lentiform fork sign,” commonly seen in uremic encephalopathy, emphasizes this syndrome's broad spectrum manifestations. A 19‐year‐old male, who underwent bilateral lung and liver transplantation, experienced a bilateral tonic–clonic seizure of unknown onset 47 days post‐surgery. MRI findings revealed an unconventional PRES pattern, featuring the “lentiform fork sign” as bilateral symmetrical vasogenic edema in the basal ganglia, surrounded by a hyperintense rim outlining the lentiform nucleus bilaterally. Subsequent management, including ISD modification and magnesium supplementation, resulted in clinical and neuroimaging resolution. An almost complete clinical and radiological resolution was achieved after 14 days. The occurrence of PRES in transplant recipients highlights the intricate interplay among ISDs, physiological factors, and cerebrovascular dynamics, potentially involving direct neurovascular endothelial toxicity and disruption of the blood–brain barrier. Neuroimaging plays a pivotal role in diagnosis. The distinctive “lentiform fork sign” was observed in this patient despite the absence of typical metabolic disturbances. Management strategies usually involve reducing hypertension, discontinuing ISDs, correcting electrolyte imbalances, and initiating antiseizure drugs if necessary. Identifying the presence of the “lentiform fork sign” alongside typical PRES edema in a patient lacking renal failure emphasizes that this manifestation is not solely indicative of uremic encephalopathy. Instead, it might represent the final common pathway resulting from alterations in the blood–brain barrier integrity within the deep white matter. Understanding such atypical imaging manifestations could significantly aid earlier and more precise diagnosis, influencing appropriate management decisions.

identifiable MRI patterns, often demonstrating vasogenic edema in the bilateral parieto-occipital white matter.Identifying unique presentations, such as the recently observed "lentiform fork sign," commonly seen in uremic encephalopathy, emphasizes this syndrome's broad spectrum manifestations.A 19-year-old male, who underwent bilateral lung and liver transplantation, experienced a bilateral tonic-clonic seizure of unknown onset 47 days post-surgery.MRI findings revealed an unconventional PRES pattern, featuring the "lentiform fork sign" as bilateral symmetrical vasogenic edema in the basal ganglia, surrounded by a hyperintense rim outlining the lentiform nucleus bilaterally.Subsequent management, including ISD modification and magnesium supplementation, resulted in clinical and neuroimaging resolution.An almost complete clinical and radiological resolution was achieved after 14 days.The occurrence of PRES in transplant recipients highlights the intricate interplay among ISDs, physiological factors, and cerebrovascular dynamics, potentially involving direct neurovascular endothelial toxicity and disruption of the blood-brain barrier.Neuroimaging plays a pivotal role in diagnosis.The distinctive "lentiform fork sign" was observed in this patient despite the absence of typical metabolic disturbances.Management strategies usually involve reducing hypertension, discontinuing ISDs, correcting electrolyte imbalances, and

| INTRODUCTION
The posterior reversible encephalopathy syndrome (PRES) presents as focal neurological symptoms associated with neuroimaging of brain edema, frequently evolving toward remission.It typically manifests as a transient episode of encephalopathy, seizures, and visual disturbances within specific patient populations.Originally described in patients with autoimmune conditions, it also occurs in solid organ transplant (SOT) recipients, possibly due to the effect of immunosuppressive drugs (ISDs). 1 In these conditions, presumed damage to the blood-brain barrier results from endothelial dysfunction caused by exposure to the toxic effects of these agents, or is precipitated by cerebrovascular dysregulation following acute hypertension. 2ommon brain magnetic resonance image (MRI) patterns associated with PRES include vasogenic brain edema in the white matter, with a dominant parietooccipital pattern, bilateral watershed pattern, or superior frontal sulcus pattern.However, atypical localizations such as frontal, temporal, basal ganglia, brainstem, or cerebellar involvement can also occur. 3][6][7] In this report, we present a case of a recent bilateral lung and liver transplant recipient with a diagnosis of cystic fibrosis who experienced his first-ever seizure episode, reflecting PRES with an atypical neuroimaging pattern, including the lentiform fork sign.

| CASE HISTORY
A 19-year-old male patient presented to the Emergency Department with an unclear onset seizure progressing to a bilateral tonic-clonic episode lasting approximately 1 mi, followed by an extended postictal state.His medical history included recent bilateral lung and liver transplantation (47th day) due to cystic fibrosis and cirrhotic liver disease, without complications.Notably, the family reported a 48-h history of headache, nausea, and vomiting preceding the seizure.Upon admission, he was receiving ISDs (tacrolimus), antibiotics, and prophylactic antivirals.
Instead, it might represent the final common pathway resulting from alterations in the blood-brain barrier integrity within the deep white matter.Understanding such atypical imaging manifestations could significantly aid earlier and more precise diagnosis, influencing appropriate management decisions.

K E Y W O R D S
brain edema, immunosuppressive drugs (ISDs), lentiform fork sign, reversible posterior encephalopathy syndrome (PRES), seizures, transplant recipient atypical, and fungal pathogens were performed, showing negative results.MRI displayed extensive bilateral symmetrical vasogenic brain edema in basal ganglia and bilateral subcortical areas, involving the diencephalon and pontine-medulla junction, with a recognizable lentiform fork sign (Figure 2).Methanol or ethylene glycol intoxication, abnormal neurodevelopment, and familial metabolic disorder symptoms were ruled out through patient history and interrogation.
Therapeutic measures included urgent magnesium replacement, and switching immunosuppressive drugs from tacrolimus to cyclosporine.Antiseizure treatment with levetiracetam was initiated on the same day during the extended postictal state due to suspicion of status epilepticus.

| OUTCOME AND FOLLOW UP
By Day 2, the patient became asymptomatic, indicating improvement in neurological condition, with no recurrence of epileptic seizures and subsequent normal EEG results (three in the following days).Before discharge, 14 days after the first assessment, a follow-up brain MRI was performed, revealing an almost complete resolution of the previously described findings (Figure 3).After discharge, the patient remained seizure-free, with a normal brain MRI (Figure 4) and EEG results performed 2 years after the initial episode.In this context, the decision was made to discontinue his antiseizure medication.
Given the clinical presentation and neuroimaging findings, the case was interpreted as an atypical PRES in

F I G U R E 2 Brain Magnetic
Resonance Imaging revealing extensive hyperintense lesions in T2 and FLAIR sequences, hypointense in T1, involving bilateral subcortical and periventricular posterior regions, with pontine medulla junction involvement compatible with vasogenic edema.The hyperintense rim that delimits the lentiform nucleus suggests the lentiform fork sign.No diffusion restriction was observed.a liver and lung transplant recipient, in the context of elevated tacrolimus plasma concentrations associated with hypomagnesemia.The patient achieved clinical and radiological resolution, with no further complications over 4 years of follow-up by now.

| DISCUSSION
PRES in transplant recipients reveals complex interactions between ISDs, physiological factors, and cerebrovascular dynamics, potentially causing direct neurovascular endothelial toxicity and blood-brain barrier disruption.PRES occurs in 1% of adult liver transplant and 2% of lung transplant recipients, with seizures as the most common clinical presentation. 1,8The patient's regimen of ISD usually plays a role, especially when it involves tacrolimus (calcineurin inhibitors), which is recognized as a frequent culprit in PRES development and seizure triggers.These toxic effects may arise due to systemic hypertension and also as a direct neurovascular endothelial toxicity effect.Moreover, as found in our patient, tacrolimus has a significant effect on urinary magnesium wasting, possibly leading to hypertension and encephalopathy after transplantation. 9,10he lentiform fork sign denotes bilateral symmetrical vasogenic brain edema in the basal ganglia, enclosed by a hyperintense rim in T2-weighted images (T2-WI) and fluid-attenuated inversion recovery (FLAIR) sequences.It is commonly observed in metabolic disturbances, such as uremic encephalopathy, diabetes mellitus, and methanol or ethylene glycol intoxications.Neuroimaging played a crucial role in this case without those metabolic alterations, with CT and MRI scans revealing this characteristic sign in typical PRES edema.As recently described in the literature, neither uremia nor metabolic acidosis was observed in this case. 4,6As implicit in the acronym PRES, the findings associated are typically reversible, showing a return to normal clinical and imaging results once the underlying cause is addressed and corrected.However, in certain instances, regions with limited diffusion can lead to lasting damage to the brain tissue. 11In our case, the patient exhibited vasogenic brain edema in an infrequent distribution without restricted diffusion or microbleeds.The patient underwent rapid and substantial almost complete recovery within 2 weeks, followed by complete resolution before 14 days of in-hospital follow-up.
The acute management of PRES involves supportive measures, primarily addressing and correcting the underlying causes, including a gradual reduction of acute hypertension, discontinuation, and/or switching ISDs, with treatment of the eventual electrolyte imbalances. 12andomized trials for treatment options are lacking, and guidelines are based on consensus.In our case, antiseizure drug therapy was initiated in the acute phase due to the suspicion of status epilepticus and continued due to the high risk of recurrence.It was discontinued once the brain edema resolved and the patient had a long seizure-free period with normal EEGs controls.Long-term antiseizure medication is usually unnecessary for most patients post-PRES, with discontinuation considered after the acute phase.
Our understanding suggests that distinctive vasogenic brain edema affecting the basal ganglia, referred to as the lentiform fork sign, does not stem from a singular metabolic origin but might represent a final common pathway resulting from compromised blood-brain barrier integrity in the deep white matter.
Our case suggests that the lentiform fork sign, previously associated with uremic encephalopathy, can occur without typical metabolic disturbances, indicating a broader spectrum of PRES presentations.Prompt recognition of such atypical features is essential for accurate diagnosis and optimal management.
Ongoing research and consensus-based guidelines are vital for enhancing our understanding and management of PRES in transplant recipients, ensuring timely intervention, better outcomes, and minimizing long-term neurological consequences.
The author has obtained written informed consent from the patient before submission.

F I G U R E 1
Computed Axial Tomography of the skull showing extensive bilateral subcortical basal and periventricular hypodensity with extension into the diencephalic and pontine-medulla junction regions, along with a mild mass effect on the frontal horn of the lateral ventricle.

F I G U R E 4
Normal Brain MagneticResonance Imaging of the same patient, with no vasogenic edema or sequelae.F I G U R E 3 Brain MagneticResonance Imaging displaying a hyperintense lesion in the protuberance, the posterior limb of the left internal capsule, and the homolateral frontoinsular subcortical region in T2 and FLAIR sequences, compatible with vasogenic edema in resolution.